Anti Malaria

ANTIMALARIA

Oleh :

Faizal Hermanto, S.Si., M.Si., Apt.

Out line Presentation

• Pendahuluan• Konsep pengobatan antiparasit• Siklus hidup Plasmodium• Morfologi Plasmodium• Jenis malaria• Diagnosa • Prinsip Terapi Antimalaria

PENDAHULUAN

Konsep Pengobatan Antiparasit

Manusia

Obat Parasit

Pendahuluan

• Etiologi Malaria Mala = buruk Aria = udara

• Malaria adalah penyakit infeksi dengan demam berkala yang disebabkan oleh parasit Plasmodium dan ditularkan oleh nyamuk anofeles betina

Statistik Malaria

• Setengah dari populasi dunia berada pada risiko malaria• Setiap tahun terjadi sekitar 250 juta kasus malaria • Setiap tahun terjadi hampir satu juta kematian.

World Health Organization, Geneva, 2009

Plasmodium

• Termasuk kedalam protozoa

• Plasmodium dapat menginfeksi : - Hewan pengerat/rhodent (P. berghei, P. Yollie) - Primata (P. Knowlesi) - Manusia (P. vivax, P. ovale, P. malariae, P. falciparum)

Siklus Hidup Plasmodium

9Gambar : siklus hidup pasmodium sp

Mengapa plasmodium tidak dapat diatasi oleh sistem imun manusia ???

Morfologi Plasmodium

Plasmodium falciparum Plasmodium malariae

Plasmodium vivax Plasmodium ovale

Stadium Eritrositer P. falciparum

Cincin Tropozoit Schizont

Jenis Malaria

Jenis malaria dan gejalanya

• Malaria tropika disebabkan oleh Plasmodium falciparum. Gejala yang timbul berupa berkurangnya kesadaran dan demam yang tidak menentu, yang kadangkala berlangsung terus menerus dengan suhu rektal di atas 48 ºC. Jenis malaria ini paling ganas dan berbahaya coz jumlah merozoit banyak, rosseting & sitoadheren.

Jenis malaria dan gejalanya

• Malaria tersiana disebabkan oleh plasmodium vivax atau ovale. Ciri-cirinya demam berkala tiga hari sekali dengan puncak 48 jam. Malaria tersiana tidak bersifat mematikan, meskipun tanpa pengobatan tetapi sering kali terjadi kambuh.

• Malaria kwartana yang disebabkan oleh Plasmodium malariae mengakibatkan demam berkala empat hari sekali, dengan puncak demam setiap 72 jam.

Kekambuhan

• Recrudescense kekambuhan yang terjadi dalam masa 8 minggu setelah berakhirnya serangan primer.

• Recurrence kekambuhan yang terjadi dalam masa 24 minggu setelah berakhirnya serangan primer.

• Relapse kekambuhan yang terjadi dalam masa 5 tahun.

Diagnosa

Diagnosa

• Mikroskopik

• Isotopic

• Parasit laktat dehidrogenase (pLDH)

• Histidin Rich Protein-2 (HRP-2)

Mikroskopik

• Pemeriksaan dengan menggunaan apusan darah tipis dan tebal dengan pewarnaan Giemsa.

• Pemeriksaan persentase parasitemia dilakukan dengan mikroskop cahaya dengan perbesaran 1000 x dan dilakukan per 1000 eritrosit.

(%) Parasitemia = Jmlh eritrosit yg terifeksi X 100% 1000 eritrosit

Prinsip Terapi

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Prinsip terapi penyakit Malaria1. Resistensi Klorokuin?2. Harus tau penyebab :

P. falciparum, P. vivax, P. ovale dan P. malariae diagnosis harus benar

3. Infeksi campuran : PF + PV4. Kepatuhan: muntah harus ulangi obat/dosis sama5. Cek berkala pengobatan tuntas kekambuhan: - muncul cepat (btk eritrosit, semua spesies), - lambat (hipnozoit: P. vivax dan P. ovale)6. Kebiasaan pend. kesehatan, kontrol vektor

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7. Untuk malaria otak/parah: Quinin/Quinidin iv s/ bisa oralmonitor fungsi jantung selama iv Q a QD

8. Masuk daerah endemik profilaksis kausal- Khemoprofilaksis klinis dan - Khemoprofilaksis Kausal (profilaksis)

9. Untuk cegah kambuh: Primakuin (s/14 hari) setelah travel

10. Kondisi patologi: - wanita hamil, - insufisiensi ginjal, hati, dll

Prinsip terapi penyakit Malaria

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KLASIFIKASI ANTIMALARIA

Skhizontosida jaringan: eliminasi perkembangan dan bentuk dormant di hati - S. J. primer (preventing RBC infection, p. causal)

- S. J. sekunder (p. terminal, cegah kambuh)

Skhizontosida darah (untuk p. klinik & supresif)- Kerja cepat : Q, CQ, MQ, AQ, QHS- Kerja lambat: Antifolat, antibiotik

Gametosida kill sexual stages and prevent transmission to mosquitoes

Sporontosida: cegah transmisi malaria

Radical cure eliminate both hepatic and erythrocytic stages. Drug?

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Major antimalarial drugsDrugs Class Use

Chloroquine 4-amino-Quinoline

Treatment & chemoprofilaxis of infection with sensitive parasites

AmodiaquineTreatment of infection with some chloroquine-resistant P. falciparum strains

Quinine

Quinolinemethanol

Oral treatment of infections with chloroquine-resistant P. falciparum

QuinidineIntravenous therapy of severe infection with P. falciparum

MefloquineChemoprophylaxis & treatment of infection with P. falciparum

Primaquine8-amino-quinoline

Radical cure and terminal prophylaxis of infection with P. vivax and P. ovale

DoxycyclineTetra-cycline

Treatment (with quinine) of infection with P. falciparum; Chemoprophylaxis

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Drugs Class UseSulfadoxine-Pyrimetha-mine (Fansidar)

Folat antagonistcombination

Treatment of infectios with some chloroquine-resistant P. falciparum

Proguanil Folat antagonist

Chemoprophylaxis with chloroquine

Halofantrine Phenantren methanol

Treatment of infections with some chloroquine-resistant P. falciparum

Lumefantrine Amyl alcohol Treatment of P. falciparum malaria in fixed combination with artemether (Coartem)

Artemisinin Sesquiterpen lactone endoperoxides

Treatment of infection with multidrug-resistant P. falciparum

Atovaquone- proguanil(Malarone)

Quinone-Folat antagonist combination

Treatment & chemoprofilaxis of P. falciparum infection

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Drugs for the prevention of malaria in travelers

Drug Use Adult dosage

Chloroquine Area without resistant P. falciparum

500 mg weekly

Mefloquine Area with chloroquine resistant P. falciparum

250 mg weekly

Doxycycline Area with multidrug-resistant P. falciparum

100 mg daily

Malarone Area without resistant P. falciparum

1 tablet (250 mg Atovaquone/100 mg proguanil) daily

Primaquine Terminal prophylaxis of P. vivax and P. ovale

15 mg base daily for 14 days after travel

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TREATMENT OF MALARIA

Clinical setting Drug therapy Alternative drugs

CQ-sensitive PF and PM infections

CQ-phosphate, 1 g then 500 mg in 6 h, followed by 500 mg daily for 2 days

OrCQ-phosphate, 1 g at 0 and 24 h, then 500 mg at 48 h

-

PV and PO infections

CQ (as above), then (if G6PD normal) primaquine 26,3 mg daily for 14 d

-

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Uncomplicated infections with CQ-resistant PF

Q sulfate 650 mg 3x daily for 3-7 d

plus of the following:

Doxycycline 100 mg 2x daily for 7 d

OrClindamycin 600 mg 2x daily for 7 d

OrFansidar, 3 tab. once

MQ 15 mg/kg once or 750 mg, then 500 mg in 6-8 h

OrMalarone 4 tab (total of 1 g atovaquone, 400mg proguanil) daily for 3 d

OrArtesunate or artemether single daily doses of 4 mg/kg on day 0, 2mg/kg on day 2 and 3, 1mg/kg on days 4-7

OrHalofantrine 500 mg every 6 h for 3 doses; repeat in 1 week


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Severe or complicated infections with PF

QD gluconate 10 mg/kg IV over 1-2 h, then 0.02 mg/kg IV/min

Or15mg/kg IV over 4 h, then 75 mg/kg IV over 4 h every 8 h

(cardiac monitoring should be in place during IV; change to oral if patient can tolerate it)

Artesunate 2.4 mg/kg IV or IM, then 1.2 mg/kg very 12 h for 1 d, then everyday

Or

Artemether 3.2 mg/kg IM, then 1.6 mg/kg/d IM


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Chloroquine

• Drug of choice: – treatment & prophylaxis malaria since 1940s– Blood schizonticide (Rapid acting)– Moderate effect against gametocytes of Pv, Po, and Pm (but not for PF)– Not active against liver stages malaria parasites (except for E. histolytica)

• Mechanism of action : - concentrating in parasite food vacuoles, - preventing polymerization of the Hb breakdown product, heme,

into hemozoin.

• Resistance : – mutations in a putative transporter can be reversed by Verapamil.

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• Adverse effects CQ:- long-term used of h doses: irreversible ototoxicity, retinopathy,

myopathy and peripheral neuropathy - parenteral adm. is best avoided cardiac and respiratory arrest.

CI: – psoriasis or porphyria, abnormalitas visual field/retinal, myopathy- Considered safe in pregnancy and for young children.

• Interaction: - antacids-Mg, -Ca intefere with CQ abs.

Pharmacokinetics:• 4-aminoquinoline derivative• Phosphate salt-oral use; hydrochloride-parenteral use• Rapid, complete GI absorption; very large apparent volume of

distribution (13,000 L = significant tissue binding)• Crosses the placenta• Renal excretion (half-life 3-5 days; real excretion enhanced by

urinary acidification

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Dosing considerations:• Large volume of distribution requires a loading dose if schizonticidal CQ plasma levels are rapidly needed for management of acute attack

• Parenteral administration should proceed by slow infusion or by a series of small intramuscular doses to avoid life-threatening CQ tox.

Antimalarial activity:• Highly effective; most widely used 4-aminoquinoline for chemoprophylaxis• Used to treat attacks of Pv, Po, Pm, and sensitive strains of PF malaria• Somewhat effective against gametocytes of Pv, Po and Pm but not against those of Pf• Not active against preerythrocytic plasmodium• Does not provide radical cures of Pv or Po {does not eliminate persistent liver parasitic stages}

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Adverse Effects CQ

• Generally well tolerated during chronic administration (prophylaxis/treatment);

• Uncommon Side-effects include:– Gastrointestinal symptoms, headache, pruritus (particularly in

black individuals), anorexia, blurred vision,

• Possible long-term effects (> 100 g accumulated)– Opthalmological/neuromuscular effects– Recommendations: periodic evaluations relative to baseline

levels– Retinal/visual fields changes or muscular weakness:

discontinue medication

• Cardiovascular ECG changes-T-wave alterations; QRS complex widening

• Intramuscular injections (large dose, 10 mg/kg) & intravenous infusion: severe hypotension, respiratory & cardiac arrest

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Contraindications/cautions:

CI in patients with:– CQ psoriasis-may cause acute attacks

» CQ should not be used in combination with other agents which may cause dermatitis

– porphyria-chloroquine (Aralen) may cause acute attacks– retinal/visual fields abnormalities

{consider risk-benefit in prescribing decision}• Cautious Use in patients with:

– hepatic damage, alcoholism, neurologic or hematologic disorders

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Contraindications/cautions:

Drug-drug pharmacokinetic effects:

– antacids + antidiarrheal drugs (kaolin, magnesium trisilicate, calcium carbonate)

decision should not be taken within about four hours before or after CQ (Aralen).

• During pregnancy:– no reports of teratogenic effects– considering risk vs. benefit:

CQ benefits appear to outweigh possible fetal risks– Oral CQ: safe for children

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Clinical Uses: Acute malarial attacks by Pv, Po, Pm and Pf (not CQ-resistant)

– Termination by CQ of fever 24-48 hoursparasitemia 48-72 hours

– Indications for parenteral CQ: vomiting precludes oral route peripheral asexual parasitemia > 5% presents of cerebral malaria

– Cure for Pv and Po malaria requires primaquine concurrent administration to eliminate persistent liver stages.

– Alternative to CQ: - hydroxycholoroquine

Chemoprophylaxis: CQ-preferred agent for prophylaxis against all forms of malaria {except where Pf exhibits resistance to 4-aminoquinolines

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Clinical Uses:

Amebiasis:– CQ + emetine (generic): alternative for amebic hepatic abscess

• Autoimmune Disease:– Long-term CQ (or hydroxycholoroquine): reported useful for

management of autoimmune disorders

CQ-Resistance: unknown mechanism probably similar to resistance described for multidrug-resistant cancer cells (membrane P- glycoprotein pump) in vitro resistance reversible by verapamil and desipramine

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MEFLOQUINE (LARIAM)

Overview: Synthetic, 4-quinoline methanol derivative (related to quinine) Oral Route of Administration only (local irritation upon injection) Highly plasma protein-bound Hepatic clearance; very slow elimination; half-life = 13-33 days

Antimalarial Properties:• Blood schizonticidal activity against: Pf & Pv• Inactive against Pf gametocytes or hepatic stages of Pv• Mechanism of action: unknown

– Resistance has been reported- Quinidine-like cardiac effects

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Clinical Uses (MQ): Prophylaxis of CQ-resistant P. falciparum strains

– effective against most CQ & pyrimethamine-sulfadoxine resistant Pf – Curative protocol: 4 weeks after leaving an endemic region; used in

this way-prophylaxis provided against Pv and probably against Po and Pm

– Curative protocol for Pv & Po necessitates the addition of primaquine (against hepatic stages)

– MQ should be only used in malarious regions where CQ is not effective.

Treatment of CQ-resistant P. falciparum– Oral treatment of mild-moderate MQ-susceptible Pf infection– Less rapid onset of action compared to Q or quinidine-suggesting that these drugs should not be used in treating severe illness.

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Adverse Reactions (MQ)• Minor/transient adverse reaction, including gastrointestinal disturbances, syncope, extra-systoles.• Transient thrombocytopenia, leukocytosis, and aminotransferase elevation• Transient neurological reactions {convulsions, depression, psychoses}• Symptoms are more likely to occur at doses > 1000 mg -frequency = as high as 1%

CI MQ Contraindicated in patients with a history of:

– epilepsy– psychiatric disturbance– cardiac conduction anomalies– quinidine (and related compound) sensitivities

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CI of MQ• Not appropriate for use in children under 15 kg or under two years of age {poorly tolerated/unsubstantiated efficacy in this group}

• Probably should not be used during first trimester of pregnancy

• Women of child-bearing age: use precautions against pregnancy for at least three months following last dosage of MQ.

• Neuropsychiatric disturbance development during MQ treatment: indication for cessation of MQ

• MQ may induce seizures in patients taking anticonvulsant medications (e.g. valproic acid & divalproex sodium).

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PRIMAQUINE

Overview: • synthetic, 8-aminoquinoline derivative• well absorbed orally• completely metabolized & excreted in the urine• major metabolite (carboxyprimaquine) accumulates with daily dosing

– primaquine and/or one of its metabolites: responsible for clinical activity

Antimalarial Properties• Activity profile

– Active against late hepatic stages {hypnozoites & schizonts of Po,Pv} provides radical cure in these cases

– Highly active against primary exoerythrocytic Pf stages– Prophylaxis (with CQ): protective against Po & Pv– Highly gametocidal against Pv, Po, Pm & Pf

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Mechanism of action PQ• antimalarial activity may be secondary to quinoline-quinone oxidants

Adverse Effects: • Few major side effects

– some gastrointestinal disturbances, headache• More serious side effects include (rare):

– leukopenia/agranulocytosis• Normal Doses:

– limited hemolysis (noted by urinary darkening/ reddening)

– significant hemolysis, methemoglobinemia (cyanosis evident) in patients with variance of glucose-6 phosphate dehydrogenase or certain other erythrocyte pentose phosphate pathway abnormalities.

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Clinical Uses of PQ• Terminal Pv & Po Malaria Prophylaxis– PQ + a blood schizonticide (typically CQ) may allow a radical cure {terminal prophylaxis} due to effects on persistent hepatic stages

• Radical cure of acute Pv & Po Malaria:– PQ + CQ: used to treat these infections (2 week primaquine duration typical)

• Gametocidal Action:– Single PQ dose causes Pf gametocides to become noninfective

• Pneumocystis carinii Pneumonia:– Clinical Features»"The symptoms of P. carinii pneumonia (PCP) include dyspnea, non-productive cough, and fever. Chest radiography demonstrates bilateral infiltrates. Extrapulmonary lesions occur in a minority (<3%) of patients, involving most frequently the lymph nodes, spleen, liver and bone marrow. Typically, in untreated PCP increasing pulmonary involvement leads to death"-CDC

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Other pharmacological effects of PQ• myeloid suppression (high doses)• may affect erythrocytes (standard doses but in genetically susceptible

individuals)

Resistance• Primaquine relative resistance in some Pv strains

CI/cautions:• Primaquine should not be used in patients:

– Currently taking quinidine– Having connective tissue abnormalities– who have history of methemoglobinemia or

granulocytopenia– who are pregnant (definitely not during first trimester)

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SULFONAMIDES & SULFONES

Overview: - Blood schizonticidal activity against Pf (some strains)

Mechanism: - Dihydrofolic acid synthesis inhibition - Weak effects against blood schizonts of Pv - Inactive against immunocytes or liver stages of Pf or Pv. - Synergistic blockade of folic acid synthesis following combination of

sulfones or sulfonamide with an antifols

• For management of CQ-resistant P. falciparum– pyrimethamine-sulfadoxine (Fansidar) or– pyrimethamine-dapsone

– Major disadvantage: sulfonamides and sulfones exhibit slow onset blood schizonticidal

activity as well as significant adverse effects.

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• Pyrimethamine-sulfadoxine (Fansidar)– Pharmacokinetics:

• Fansidar-well absorbed• Renal route of excretion

– Antimalarial Activity/Resistance:• Effective against falciparum malaria (some strains)• For serious cases, quinine is given concurrently since

Fansidar activity develops slowly• Ineffective against vivax malaria

Sulfonamides & Sulfones

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QUININE

• Overview: Quinine-alkaloid from the bark of the cinchona tree

Pharmacokinetics- rapid absorption; wide tissue distribution- elimination halftime: normal individuals: 7-12 h ; 8-21 h in malaria infected patients- hepatic metabolism (80%)- urine excretion- Effective concentration range:

• ineffective < 2 ug/mL• > 7 ug/mL-associated with "cinchonism"• narrow therapeutic range: frequent side effects associate with falciparum malaria management with Q.

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QUININE

Antimalarial activity– rapid onset; highly effective blood schizonticide against the four malarial parasites: Pv, Po, Pf, and Pm.– Gametocidal for Pv & Po; not very effective as a gametocidal agent for Pf

gametocytes– No effect on sporozoites or liver stages of any parasite.

Pharmacological effects– Oral use: gastric irritation– Myocardial effects similar to Q, but quinine's effect less intense– Skeletal muscle: curare-like effect; lengthened skeletal muscle membrane refractory.– May be used to reduce contracture of myotonia congenita.– Slight oxytoxic effect (especially third trimester time frame)– With therapeutic doses: occasional hypoglycemia {secondary to pancreatic B-cell insulin release}-especially prominent in patients who are pregnant or with severe infections.

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QUININE

Clinical Uses – Parenteral treatment: severe falciparum malaria

• slow, intravenous administration• alternative: dilute intramuscular injection acceptable

– Oral treatment of falciparum malaria (CQ-resistant)• management (with other drugs) for acute Pf-CQ resistant malarial attacks• Q alone will not eliminate the infection {will reduce parasitemia, however}• Q-less effective than CQ; Q not used to manage acute attacks of Po, Pv, Pm or CQ-sensitive Pf malaria

Prophylaxis: Q generally not used, Exceptions:– P. falciparum CQ resistance and mefloquine; – doxycycline - unavailable

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QUININE

Other Uses• nighttime leg cramps• Q + clindamycin: for management in cases of severe babesiosis (Babesia microti)http://www.dpd.cdc.gov/DPDx/HTML/Babesiosis.htm

Resistance:– resistance for monotherapy increasing; therapeutic failure

due to resistance of Q + second-drug has not been confirmed.

http://www.dpd.cdc.gov/DPDx/HTML/Babesiosis.htm

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QUININE

Adverse Effects– Gastrointestinal Effects: nausea, epigastric pain, vomiting– Cinchonism:

• occurs if plasma levels > 7-10 ug/mL• symptoms:-if symptoms do not abate, discontinue Q and obtain blood level.

– slight visual disturbances, - mild tinnitus, - dizziness– Headache, - nausea

– Hematologic effects:• Rare: (0.05%): hemolysis; they also occur in patients with glucose-6-phosphate dehydrogenase deficiency• Rare: leukopenia, thrombocytopenic purpura, hypoprothrombinemia,

agranulocytosis, Schonlein-Henoch purpura– Hypoglycemia:

• may occur at therapeutic doses; glucose administration may result and further insulin release and hypoglycemia exacerbation.

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QUININE

Other Toxicities:• IV quinine-rare thrombophlebitis• rapid IV infusion: hypotension, seizures, ventricular fibrillation, death• congenital malformation if large-doesquinine in failed abortion• severe toxicity: rare {may include -- fever, deafness, visual abnormalities, CNS effects including syncope & confusion, quinidine-like effects}

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QUINIDINE GLUCONATE

Overview– Dextrorotatory diasteriomer of quinine – Quinidine gluconate - typically used for management of

cardiac arrhythmias• Also used for parenteral treatment of severe malaria, when parenteral

quinine form is unavailable {note: in the United States, parenteral form of quinine, quinine hydrochloride is unavailable}

– IV quinidine gluconate: adverse effects, cautions, and CI• rare: thrombophlebitis

• potentially cardiotoxic-consider risk vs. benefit ratio if administration to a patient with cardiac conduction hepatic or renal abnormalities

• generally contraindications/caution or quinidine gluconate similar to that for quinine

Terimakasih

Anti Malaria

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